Noninvasive Techniques

Esophagograms with careful evaluation of the cervical esophagus can indirectly visualize parathyroid tumors.⁴¹⁹ Ultrasonography with high resolution, real-time technology is an excellent noninvasive technique, although its overall results are operator dependent.⁴¹⁸ Also the retroesophageal, retrotracheal, and mediastinal areas cannot usually be well assessed.⁴¹⁸ Computed tomography (CT) scanning can readily visualize these areas and also evaluate the extent of disease in patients with parathyroid carcinoma. Scintigraphy, formerly using radionuclides as selenomethionine-75 or gallium-67 citrate, has been improved by computer subtraction techniques. The sequential use of thallium-201, which concentrates both in para-thyroid and thyroid, and of technetium-99m, which concentrates in the thyroid, followed by subtraction allows imaging of the parathyroid tumors.⁴¹⁸ It has good sensitivity, but its specificity can be affected by concomitant thyroid diseases, including adenomas and carcinomas (sometimes associated with parathyroid carcinoma). Thallium-201 can also accumulate in metastatic cancer to lymph nodes. Magnetic resonance imaging (MRI) is improving but at this time does not appear superior to CT. In a prospective comparison based on 100 patients with benign parathyroid tumors before surgery, overall sensitivities were as follows: scintigraphy 73%, CT 68%, MRI 57%, sonography 5 55%, with respective specificities of 94, 92, 87, and 95%.⁴²⁰ None of these imaging techniques had a sensitivity of more than 50% for small (< 250 mg) tumors, and sensitivity also decreases in patients who had previous surgery to the neck.

For patients with parathyroid carcinoma, CT scanning appears most useful at this time since it has a good sensitivity in detecting the primary tumor and allows evaluation of its local extent and metastases. Technetium-99m-sestamibi scanning, previously used for myocardial perfusion studies, has been recently introduced for parathyroid imaging.⁴²¹ A high sensitivity of up to 80% to 90% has been observed in detecting abnormal glands. Its evaluation in parathyroid carcinoma is in progress.

Invasive Techniques

They require highly skilled personnel and are currently indicated for difficult cases only. Venography with venous samplings for iPTH remains one of the most sensitive techniques.⁴¹⁸ It measures PTH from the venous effluents (thyroid veins) before the hormone is degraded in the peripheral blood. A unilateral gradient is in favor of a single adenoma or carcinoma, whereas a bilateral gradient usually indicates diffuse hyperplasia. Multiple venous samples are usually taken, including the vertebral, thymic, and internal mammary veins in addition to the thyroid veins. It is a time-consuming but relativity safe procedure.

Angiographic studies have been obtained with a number of techniques and are rarely indicated today. Selective or superselective angiography necessitates experienced personnel. Nonectopic parathyroid glands are supplied by branches of the inferior thyroid artery, which originates from the thyrocervical trunk. Instances of severe neurologic complications, quadriplegia, and even death can occur by inadvertent injection of contrast material into spinal branches of the thyrocervical trunk or the costocervical trunk.⁴²² Safer but less sensitive techniques include nonselective intra-arterial or intravenous digital subtraction angiography.⁴¹⁸ Angiography has also been used to ablate functioning parathyroid tumors by direct injection of contrast material.⁴²²

Sonography or CT can also guide percutaneous fine needle biopsy for diagnostic purposes, and some authors have even ablated functional tissue by direct injection of ethanol. The possible risks of these biopsies is spillage of cells, which in the case of carcinoma can lead to recurrent tumors.³⁸⁴ Even in cases of benign parathyroid adenomas, recurrent adenomas (“parathyromatosis”) have been described following spillage. The diagnosis of primary hyperparathyroidism is clinical and biochemical. Biopsy is not necessary in the majority of cases before definitive surgery for either benign or malignant parathyroid tumors and is in fact generally contraindicated.

Surgery

Surgery is the major and only curative treatment of parathyroid carcinoma. It requires an impeccable technique, and the initial operation is the most important one.³⁸⁴ Removal of the tumor en bloc, with all involved surrounding structures and without violating its capsule is mandatory. For Wang and Gaz, all cases where the tumor capsule was violated had local tumor recurrence.³⁸⁰ Often, the surgeon will rely on the gross appearance to suspect a carcinoma: presence of a thick fibrous capsule with local adherences, gray-white color, and hard consistency, as opposed to the soft reddish brown appearance of adenomas. Simple biopsy with frozen sections should not be attempted in view of its unreliability in distinguishing benign from malignant lesions and its risk of tumor seeding.^384,442 The surgical specimen should include all areas of local adherence such as the ipsilateral thyroid lobe and isthmus, involved strap muscles, and blood vessels. If the recurrent laryngeal nerve is involved, it should be sacrificed as well, since attempts to dissect it from the tumor carry the risk of local recurrence.³⁸¹ Occasionally, the trachea and/or esophagus may be involved as well. Biopsy of the lymph nodes of the tracheoesophageal groove should be performed. Lymph node metastasis is uncommon during initial surgery and if not present most authors do not recommend a prophylactic radical neck dissection.^380,384 When the gross distinction with a benign enlargement is in doubt, the other ipsilateral parathyroid should be removed as well to rule out the possibility of diffuse hyperplasia.

Close monitoring after surgery is essential to detect hypocalcemia (“hungry bone” syndrome), which is usually temporary but may require supplements of calcium and vitamin D.⁴⁴³

The 5-year survival is about 50% (including 30% without recurrence) and the 10-year survival varies from 13 to 35%.^381,382,402 Parathyroid carcinomas tend to grow slowly and metastasize late. The presence of mitosis or vascular invasion has not been useful in predicting prognosis.³⁸² Early recurrence, however, seems to be an unfavorable factor. Most recurrences occur within 2 to 3 years following initial surgery. Since the disease grows slowly, and most patients die from metabolic complications of hyperparathyroidism rather than tumor burden, an aggressive surgical approach for recurrent or metastic disease is advisable.^381,382 Patients may survive many years despite repeated recurrences and metastasis.⁴⁰² Local recurrences are common (30%), as well as metastases to cervical lymph nodes (30% to 40%). Distant metastases involve most commonly lungs (20% to 40%) but also other sites, including mediastinum, bone, pleura, pericardium, and pancreas.^380,381,402

Systemic Therapy

Parathyroid carcinomas are resistant to radiotherapy, although it can occasionally be useful for palliation of pain from bone metastasis.⁴⁴⁴ There is little experience with systemic therapy.⁴²³ Partial and temporary remissions were observed with hormonal therapy, including estrogens and testosterone. A partial remission of 10 months duration was reported with “Hexestrol,” a synthetic estrogen compound (phenol, 4,4′-(1,2-diethylethylene).⁴⁴⁵ Glucocorticoids do not appear active.⁴⁶² One patient was treated with auto-immunotherapy (portion of resected parathyroid carcinoma emulsified with Freund's adjuvant and reinjected) without response.⁴⁴⁵

Experience with chemotherapy is anecdotal. Nitrogen mustard was given to two patients without response.⁴²³ In 1981 the first successful combination chemotherapy in a patient with metastatic nonfunctioning parathyroid carcinoma was described.⁴²³ The “MACC” combination (methotrexate, doxorubicin, cyclophosphamide, and CCNU) produced a dramatic regression of a large metastatic mediastinal mass and malignant pleural effusion lasting 18 months. Cisplatin given once (50 mg/m²) at relapse produced no response. A combination of cyclophosphamide, 5-fluorouracil, and DTIC produced complete regression of pulmonary metastases and a partial biochemical response of 13 months duration in a patient with a functioning carcinoma.³⁰⁴ DTIC alone has produced a partial response with marked decrease of serum calcium and iPTH but of short duration (< 2 months) in a patient with functioning carcinoma.⁴⁴⁷ Another case of nonfunctioning carcinoma was treated with a modification of the MACC protocol (mitoxantrone substituted for doxorubicin) and had a partial response for 101 months.⁴²⁴

Pathologic Considerations

MTC is a neoplasm of the calcitonin-secreting C-cells, which are sparsely distributed in the thyroid gland.⁴⁶² In approximately 80% of patients, MTC occurs as a sporadic tumor with a unilateral origin in the thyroid. In 20% of patients, however, the neoplasm occurs in an autosomal dominant genetic syndome, of which there are three or more that may involve other endocrine and neural lesions. In these inherited forms, MTC arises as multifocal, bilateral tumors in the thyroid.

Patients with the sporadic form of MTC present with palpable thyroid nodules and almost always have cervical lymph node involvement. MTCs are well-demarcated, whitish, firm nodules that, microscopically, consist of sheets or nests of polygonal cells separated by variable amounts of fibrous stroma (Figure 89-7). Often the tumors stain positive for amyloid. The hallmark histologic feature of MTC, however, is positive immunostaining for the peptide hormone, calcitonin, which is the major biochemical product of normal thyroid C-cells. The presence of calcitonin can help make the diagnosis of MTC when patients present with one of the several variant histologic forms that have been described.⁴⁶³ Immunostaining for calcitonin is also necessary for the diagnosis of the precursor lesions for MTC, which occur bilaterally in the genetic forms of this tumor discussed in more detail below.

Figure 89-7

Histologic features of medullary thyroid cancer. A, Nests of polygonal cells. B, Spindle-shaped cells. C, Amyloid deposits (arrows). D, Large amount of fibrous stroma with sparse cells and amyloid nodules (arrows) (reproduced with permission from Mendelsohn (more...)

Biologic Characteristics

By far the most striking biologic characteristic of MTC is the occurrence of this neoplasm in a multifocal pattern in autosomal dominant genetic syndromes.⁴⁶⁴ The molecular basis for these genetic forms of MTC is not yet understood, but the known chromosomal changes and stages for development of the tumors are discussed below in the section on inherited MTC.

The molecular basis for the loss of differentiation in the aggressive forms of MTC is not yet fully established. In contrast to many solid tumors, chromosomal changes in MTC, such as frequent allelic deletions, are not common.^465,466 Although several investigators have implicated chromosome 10 the only consistent abnormalities appear to be deletions on the short arm of chromosome 1, and these could be involved with tumor progression rather than initiation.^467–472

Studies of cultured MTC cells from a patient with virulent MTC indicate that whatever chromosome regions are involved, a deficient activation of one or more cellular signal transduction pathways may be a key step in progression of MTC. Activation of either the protein kinase C or protein kinase A pathways can partially differentiate cultured MTC cells as manifested by an increase in transcription of the calcitonin gene and slowing of cell growth.⁴⁷³ A virtually complete differentiation response can be elicited in these same cells by insertion of a mutated Harvey ras oncogene.⁴⁷³ In this situation, not only is there an increase in calcitonin gene expression, but the mRNA splicing for the resultant transcripts resembles the pattern of mRNA splicing in the normal thyroid C-cell. In addition, the cells acquire the typical mature neurosecretory granules of APUD cells, which are lacking in the control cultured cells. The final mediators of this response to an inserted ras gene are being investigated, but a coordinated increase in the protein kinase A and C pathways, plus other signal transduction input, is probably involved. A marked increase in expression of the c-jun oncogene, which is known to participate in multiple protein kinase C mediated events, accompanies the ras gene induced differentiation of the MTC cells.⁴⁷³ Presumably, the increase in this transcription factor activates a series of other transcription factors that mediate maturation of the cells.

Surgical Management

Sporadic MCT usually presents as a solitary nodule in the upper half of the lateral lobe on either side, although in some cases, a metastatic lymph node may be detected first while the primary tumor remains occult to clinical examination. Currently, the diagnosis is frequently established before operation by FNA cytology, after which a basal serum calcitonin can be obtained to confirm the diagnosis (see Figure 89-9). The calcitonin level may be of value in predicting the amount of tumor present and whether lymph nodes are likely to be involved. Urinary catecholamine levels must be obtained to rule out pheochromocytoma, even when the history is negative for MEN 2a and there are no physical findings to suggest MEN 2b before a thyroidectomy is undertaken (see Figure 89-9). If present, the pheochromocytoma should always be removed prior to the thyroidectomy.

The minimal treatment of MTC is total thyroidectomy.⁴⁹⁵ In sporadic disease, this allows for excision of any intraglandular lymphatic spread and careful immunohistopathologic study of the contralateral lobe for possible C-cell hyperplasia. Even in some patients with metastases, given the fact that MTC is often slow growing, minimal treatment is a total thyroidectomy. Although not curative, this may prevent tumor growth that can impinge on major structures such as the trachea and esophagus. Most patients with sporadic disease have lymph node metastases when first diagnosed. A central lymph node compartment dissection, preserving the parathyroid glands and recurrent laryngeal nerves, is indicated. Dissection of the nodes includes the Delphian group, those around the upper pole of the thyroid lobe, those in the tracheo-esophageal groove along the recurrent laryngeal nerve and the anterior mediastinal lymph nodes to the level of the innominate artery. Some nodes contain metastases in nearly all patients with a palpable primary tumor within the thyroid gland at operation. If lateral lymph nodes are involved, a modified radical neck dissection should be done.⁴⁹⁶ Occasionally, because of invasion through the lymph node capsule and involvement of contiguous structures, a formal radical dissection may be required.

In patients with MTC, discovered by calcitonin screening and no palpable tumor, central compartment lymph nodes may be tumor free. Nevertheless, even normal-sized nodes should be sampled for frozen section examination to determine whether a complete and thorough central compartment dissection is required (see Figure 89-9). Lateral lymph node involvement is treated by modified neck dissection, which may be bilateral, performed in one or two stages. When the lateral lymph nodes are involved with MCT, a biochemical cure, as determined by calcitonin testing, is unlikely (20%). As a result, a formal (modified) radical neck dissection has been considered by many to be futile.⁴⁹⁶ Occasionally, this is still indicated if the procedure is required to excise all areas of gross disease because of lymph node invasion of local tissues. For this reason, when possible prior to initial surgery, or following surgery, computerized tomography or magnetic resonance image scans of the cervical, mediastinum, and abdominal regions should be done to document areas of discernible metastases. When calcitonin levels remain elevated despite lack of clinically evident disease after a total thyroidectomy and central compartment dissection, controversy continues as to whether a neck dissection on one, or both sides, should be done. Tissel favors a meticulous radical neck dissection and has achieved a biochemical cure in about half of a relatively small group of patients treated this way.⁴⁹⁷ Alternatively, others have favored regional excision of any palpable nodes or those suspected on the basis of a positive thallium scan or cervical ultrasound when the disease has been limited to the lateral neck or anterior mediastinum. One of the causes of failure after performing a radical neck dissection based entirely on an elevated calcitonin level is that clinically occult MTC already may have spread hematogenously to involve the liver, lungs, or bone. Therefore, it is reasonable to perform selective venous sampling for calcitonin to rule out disseminated disease before considering any extensive additional neck procedures.

Treatment of Recurrent or Metastatic Disease

When persistent, recurrent, or disseminated disease is present, MTC usually progresses slowly. Since effective radiation therapy or chemotherapy is not well established, it is important to consider several prognostic factors when deciding if chemotherapy is indicated. As discussed previously, tumors that have poor immunocytochemical staining for calcitonin tend to have a more aggressive course.^478–480 Although the serum calcitonin level correlates with the extent of disease, it does not help in identifying patients with a poorer prognosis. Rapidly rising, high serum CEA is more predictive of a rapid disease course.⁴⁹²

Recurrent tumors may be amenable to repeated surgical resection, especially for palliation of symptoms due to local tissue invasion or due to a syndrome of hormonal excess. Radiation therapy does not have an established role in the treatment of locally advanced MTC.⁴⁷⁶ In selected cases of patients with symptomatic bone metastases, a trial of radiation may offer transient palliative benefit.

Although most reports of chemotherapy for MTC are anecdotal, the experience provides some guidelines for therapeutic approaches. Since MTC belongs to the APUD family of neoplasms, a number of single agent and combination chemotherapy treatments that show activity in other “APUD-omas” have been used in advanced MTC.

Gottlieb and colleagues reported three partial remissions and resolution of disease-related diarrhea in six patients with advanced MTC following treatment with doxorubicin.⁴⁹⁸ Additional reports by others suggest an overall partial reponse rate of 30% in 46 patients with MTC treated with doxorubicin as a single agent.^499–502 The combination of streptozocin and doxorubicin was not active in a small trial of patients.^503,504 Reports of the combination of 5-fluorouracil and dacarbazine (including a complete response), doxorubicin and cisplatin, or dacarbazine, 5-fluorouracil, or etoposide used as single agents suggest limited activity for these drugs.^{501,505–510} The combination of cyclophosphamide, vincristine, and dacarbazine found to be effective in malignant pheochromocytoma, has been studied in three patients by us.^511–513 Two of these patients had a partial response demonstrated by reduced serum calcitonin and/or CEA and objective regression of radiologically demonstrated masses. The other patient had stable disease for more than 17 months. Until prospective multiinstitutional studies of chemotherapy regimens for patients with metastatic MTC are undertaken, experimental phase I or II studies should be considered for individual patients with progressive, symptomatic disease.

Since biologic response modifiers, such as the somatostatin analog, octreotide acetate, have been shown to reduce circulating hormones, halt progression, and occasionally reduce tumor size in various neuroendocrine tumors, this agent may have a role in patients with MTC.^514,515 Long-term subcutaneous injection of octreotide acetate to 21 patients with MTC reduced serum calcitonin in 11, but CEA did not change.^515,516 Flushing and diarrhea improved in some, and several patients reportedly had objective tumor response. Additional clinical studies are required to determine the activity of somatostatin analogs in patients with metastatic MTC.

Embryology and Anatomy

Chromaffin tissue constitutes one component of the diffuse neuroendocrine (APUD) system, thought to be derived from the embryonic neuroectodermal crest.^353,547 Although this embryologic origin of APUD tumors is now disputed, the common genetic and clinicopathologic characteristics of pheochromocytoma and APUD tumors justify their consideration as entities of a common neuroendocrine system.^{355,372–374} In the fetus and in infancy, diffuse paraganglionic chromaffin tissue is prominent but later regresses, aside from that found within the adrenal medulla.⁵⁴⁸ Because of this, pheochromocytomas may arise from chromaffin remnants virtually anywhere, but the vast majority (90%) are found in the adrenal medulla.^535,542 The most common extra-adrenal sites are the region where the left renal vein crosses the aorta, renal hilus, and the origin of the inferior mesenteric artery (organ of Zuckerkandl).

Pathologic Characteristics

The typical adrenal pheochromocytoma is a sporadically occurring neoplasm, arising from either gland. When detected, it is approximately 5 cm in diameter and weighs 50 to 100 g.⁵³⁵ The adrenal mass is often pseudoencapsulated, and it is highly vascularized with a beefy appearance and consistency. Larger tumors frequently contain areas of hemorrhage or empty or fluid-filled cysts surrounded by connective tissue and calcifications (Figure 89-10A). The microscopic appearance of a pheochromocytoma is similar to the architecture and morphology of normal chromaffin tissue. The cells are usually round or polygonal with abundant eosinophilic or basophilic fine granular cytoplasm and are frequently arranged in cords or clusters (Figure 89-10B).⁵³⁵ Nuclear pleomorphism and hyperchromasia are common. Mitotic figures are often seen in adrenal hyperplasia and in pheochromocytoma, but they are not necessarily prominent histological features. Chromaffin cells and pheochromocytomas show a characteristic brown staining following application of chromium salts (hence, chromaffin), although this method has largely been replaced by the Grimelius argyrophile stain.⁵⁴⁹ The demonstration of a wide array of neuroendocrine products by immunocytochemical analysis reflects the content of dense intracytoplasmic neurosecretory granules, which are apparent by electron microscopic examination (Figure 89-10C).⁵³⁵ Commonly identified products include biogenic amines, neuron-specific enzymes, and neuropeptides (Table 89-14).^{526,530,535,550–563}

Figure 89-10

Pheochromocytoma. A, Gross appearance of a surgically removed hemisected extra-adrenal pheochromocytoma. B, Histopathologic appearance of a pheochromocytoma showing typical cords of glandular cells separated by bands of stroma (hematoxylin and eosin, (more...)

Table 89-14

Biologic Markers in Pheochromocytoma.

There are no pathognomonic criteria for malignancy of a pheochromocytoma other than the natural history of an individual's tumor that manifests chromaffin cell invasion or dissemination at sites where chromaffin tissue is normally not present. Malignant tumors have a predilection for spreading to bone (predominantly to spine, ribs, and skull), lung, liver, and retroperitoneal and mediastinal lymph nodes.^{511,517,564,565} A number of studies have attempted to identify characteristics that can discriminate malignant from benign tumors.^535,566 Among these, nuclear pleomorphism, mitotic figures, vascular invasion, cortical extension, necrosis, and immunocytochemical characteristics are not particularly useful. Some authors have shown that increased tumor size and extra-adrenal location are associated with a malignant phenotype.^520,542,566 Investigations of tumor DNA ploidy by flow cytometry have demonstrated the potential utility of this technique for defining a malignant subset.^567–569 Of 62 tumors studied, approximately one-third of tumors containing aneuploid, polyploid, or tetraploid DNA were malignant, while all 18 that were diploid followed a benign course, a statistically significant difference.⁵⁶⁷ However, DNA ploidy is not discriminant for malignancy since this study and others demonstrated a high prevalence of aneuploidy in benign pheochromocytomas as well.^570–572 Sustentacular cells are dendritic cells stained positive for S-100. These cells are found in normal paraganglionic tissue and benign pheochromocytomas. Absence of these cells suggests malignancy in several studies.⁵⁷³

Biologic Characteristics

Germ line mutations of the ret oncogene have been found in lymphocytes, medullary thyroid carcinoma, and pheochromocytoma in carriers of MEN 2a and 2b ret oncogene encodes a transmembrane tyrosine kinase, but this mutation was rarely found in sporadic pheochromocytomas.^574–577 Loss of heterozygosity, which suggests loss of a tumor suppressor gene at chromosomes 1p, 3p, 17p and 22q is common in both familial and sporadic pheochromocytomas.^578–580 These molecular and cytogenetic findings suggest the development of pheochromocytoma follows the model of multistage carcinogenesis exemplified in colon cancer.

Clinical Features

There is no correlation between the amount of catecholamines produced and the severity of blood pressure changes.^526,581 Thus, patients may present anywhere in the spectrum from normotensive and asymptomatic to a severe, life-threatening hypertensive crisis causing cerebral hemorrhage, myocardial infarction, or cardiac failure.^521,582 In fact, many patients can be quite asymptomatic during their lifetime, specifically in the elderly, so that up to one-third of patients in autopsy series were not diagnosed before death.⁵⁸³ In clinically diagnosed patients, hypertension can be either sustained or episodic, and each occurs in approximately one-half of patients with pheochromocytoma. Five percent are normotensive. In rare cases, episodic hypotension is the main symptom due to secretion of predominantly epinephrine or dopamine. Hypertensive episodes may be precipitated by physical stress, an increase in intra-abdominal pressure, or by certain drugs including phenothiazine, a tricyclic antidepressant, metoclopramide, naloxone, and droperodol.^530,584 Characteristically, symptoms occur paroxysmally even in patients with sustained hypertension. The most common symptoms are headache, sweating, and palpitation; each occurs in about 60% of patients. Almost all patients have at least one or two of these three symptoms. But the positive predictive value of this triad is low because only 5.9% of hypertensive patients with this entire triad have pheochromocytoma. Other common symptoms, in decreasing frequency, are pallor, nausea, anxiety, weakness, dyspnea, visual disturbance, abdominal pain, tremor, and weight loss.⁵⁸⁵ Tachycardia, tremor, and anxiety are prominent in pheochromocytomas secreting a lot of epinephrine. Attacks of symptoms happen abruptly and usually do not last more than 15 minutes. An important feature that distinguishes hypertension of pheochromocytoma from essential hypertension (in the absence of pharmacologic therapy) is the presence of postural hypotension, manifested as a significant drop in systolic pressure in the upright position, but it happens in less than 50% of patients.^{521,526,586,587} Because of chronic vasoconstriction, the down-regulation of peripheral alpha receptors, and the presence of vasodilatory biogenic amines or peptides, such as VIP and enkephalins, patients with pheochromocytoma are commonly hypovolemic, accounting for postural blood pressure changes.^530,531,586 Cardiomyopathy and congestive heart failure due to persistently high circulating catecholamines have been reported. Pheochromocytomas in MEN patients are frequently asymptomatic, but these patients can go into hypertensive crises during surgery for hyperparathyroidism or medullary thyroid carcinoma. Therefore, all patients with MEN 2 should be carefully screened for the presence of pheochromocytoma before any surgery or invasive procedure.

Biochemical Feature

Along with other neoplasms of the diffuse neuroendocrine (APUD, amine precursor uptake and decarboxylation) system, pheochromocytomas are specialized neoplasms that can synthesize, store, and secrete biological amines and peptides. A large number of these substances have been associated with pheochromocytoma, and they are often capable of producing specific clinical syndromes (see Table 89-14).^{526,530,550–552,558–563} Chromogranin A is a soluble binding protein found in the neurosecretory granule; it is the most prevalent biologic marker for pheochromocytoma.⁵⁵⁵ This marker is not specific, however, since it is also expressed in other neuroendocrine and non-endocrine neoplasms as well.^556,588,589

Neuropeptide Y is a peptide with potent vasoconstrictor activity. High neuropeptide Y immunoreactivity has been found in both benign and malignant pheochromocytomas; by far, the most important secretory products of pheochromocytomas are the biogenic amines (Figure 89-11; Table 89-14).^590–594 The majority of these neoplasms secrete excess norepinephrine that results in sporadic or sustained hypertension.⁵¹⁹ Epinephrine is the major catecholamine secreted by normal adrenal medulla, and it is frequently elevated in pheochromocytoma, especially in familial cases, but norepinephrine predominates in most tumors.⁵⁹⁵ Dopamine and the catecholamine precursor, dihydroxyphenylalanine (dopa), are also secreted by pheochromocytomas, and there is some evidence that high circulating levels of these norepinephrine precursors are more commonly associated with a malignant phenotype.^596,597

Figure 89-11

Actuarial survival of 22 patients with malignant pheochromocytoma from the time of surgical diagnosis.

Medical Management

The mainstay of preoperativepharmacological management is α-adrenergic blockade with phenoxybenzamine in doses ranging from 10 mg twice daily up to tolerable doses that will control blood pressure, allow for restitution of normal blood volume, and block catecholamine-induced gut hypomotility (Figure 89-14).^{520,521,525,530,595,598} The major side effect is orthostatic hypotension, and reflex supraventricular tachycardias or arrhythmias may occur. The latter may be controlled with the addition of β-blocking agents such as propranolol, atenolol, or esmolol only after adequate α-blockade is established since unopposed β-blockade may worsen vasoconstriction and hypertension. Additional agents may need to be added or substituted for optimal management.⁵⁸⁶ These include α-blockers prazosin or terazosin, the combined α- and β-blocker labetolol, calcium channel antagonists (nifedipine or verapamil), and the angiotensin-converting enzyme inhibitors (captopril or enalapril).^621–624 None of these agents has any particular advantages, and some have disadvantages, so their use depends on individual circumstances and the experience of the clinician. In severe hypertension, α-adrenergic blockade with intravenous phentolamine or vasodilation with nitroprusside may be used.⁶²⁵

Figure 89-14

Algorithm for the diagnosis and management of pheochromocytoma.

Metyrosine (α-methyl-paratyrosine) is a competitive inhibitor of the rate-limiting hydroxylation step of catecholamine synthesis, and it is used in addition to α- and β-adrenergic active agents to deplete tumor catecholamines and further reduce blood pressure before surgery or in patients who have failed standard treatment or whose tumor cannot be resected (see Figure 89-12).^586,626 The starting dose is 250 mg four times daily, and it may be titrated up to 4 g per day. The central nervous system side effects of sedation, irritability, nightmares, sleep disturbance, and hallucinations are, however, often dose-limiting.

Surgical Management of Benign or Recurrent Resectable Disease

Nearly all benign pheochromocytomas can be cured by surgical resection. Because of its slow growth rate and accompanying significant morbidity, complete resection of local recurrence or limited metastases of malignant pheochromocytoma should be attempted. But the value of debulking surgery for patients whose tumor cannot be completely resected is not established.^{517,531,627,628} Most soft tissue spread including some liver metastases is amenable to resection; the majority of patients with malignant pheochromocytoma also have bone metastases as well.^511,564

Traditionally, all patients, regardless of blood pressure readings, would be prepared with an α-blocking agent or calcium channel blocker as described above to control blood pressure preoperatively.⁶²³ Induction of general anesthesia and manipulation of the tumor may provoke a release of massive amounts of catecholamines, making prior receptor blockade important. In addition, most patients have significant reduction of intravascular fluid volume, and α-blockade permits volume reexpansion. The administration of a β-blockers may not always be necessary but clearly should be given if the patient has tachycardia, arrhythmia, or a catecholamine profile showing a preponderance of epinephrine secretion. One approach is to give propranolol to most patients for 48 hours preoperatively, beginning with a dose of 10 mg four times a day. Propranolol and phenoxybenzamine may be given with a sip of water early on the morning of operation. The caveat of this approach is that it will be more difficult for surgeons to find other occult pheochromocytomas, because the clues of residual tumor, ie, persistent hypertension after resection and hypertensive response during exploration of the abdomen after tumor removal, are abolished by pre-operative preparation. With advancement in anesthesiology and intra-operative monitoring, some surgeons prefer not to prepare patients for operation with an α-adrenergic blocker. The morbidity and mortality seem to be comparable in a major center.⁴⁵⁴

The operative approach is determined by the location of the tumor(s) as determined by preoperative imaging investigations. For intra-abdominal pheochromocytomas, an anterior approach through a bucket handle or chevron upper abdominal approach is used to permit exploration of both adrenal glands and a thorough examination of the retroperitoneum for possible occult extra-adrenal pheochromocytomas with the least amount of manipulation.^{520,521,530,595,628,630,631} For MEN 2 patients, bilateral disease is common. Bilateral total adrenalectomy is associated with a lifelong requirement to manage adrenal insufficiency. In addition, malignant pheochromocytoma is very rare in MEN 2. Therefore, unilateral or bilateral subtotal resection with preservation of adrenocortical function can be considered in this population. For the control of hypertension intraoperatively, the rapidly acting direct vasodilating agent, sodium nitroprusside, nitroglycerin, phentolamine, nicardipine, or labetalol may be used intravenously as a drip when the systolic blood pressure exceeds 160 mm of Hg. The rate of infusion can be readily titrated to maintain the pressure at this level or lower. For cardiac arrhythmia or tachycardia, short acting esmolol or lidocaine is preferred. After the removal of the tumor, there may be an increase in the intravascular capacity and an acute fall in blood pressure that is best managed by intravenous fluid replacement rather than vasopressor drugs.^531,630,632 Rarely, if the patient has been well prepared, an intravenous infusion of norepinephrine may be required while volume is being restored. Transient hypoglycemia can occur after surgery because of increased insulin secretion secondary to high circulating catecholamines. Blood sugar should be monitored postoperatively.

During operative manipulation of a pheochromocytoma, great care and gentleness are required not only to avoid episodes of severe hypertension but to avoid disruption of the tumor capsule. Malignancy cannot be determined either by the gross appearance or by histopathologic studies of the primary tumor in most cases. Some patients with proven malignant pheochromoctyoma as determined by bone, liver, or lung metastases have had well-encapsulated tumors without evidence of invasion or lymph node involvement. Capsular disruption by application of instruments or rough handling can result in implantation of tumor cells even when the neoplasm is considered benign.

Most patients become normotensive after resection of pheochromocytoma, but some remain hypertensive. Urinary or plasma catecholamines or metabolites should be checked 2 weeks after surgery. If test results are normal, these patients may have concurrent essential hypertension. Otherwise, residual tumors are likely to be present.⁵⁸⁵ The median time for recurrence following primary resection of malignant pheochromocytoma is approximately 6 years and may be as long as 20 years.^{522,527,538,564} The lack of discriminating features of malignancy makes lifetime follow-up necessary for all patients.⁵⁴³ The follow-up consists of clinical and biochemical assessment several times during the first year and then a yearly test of urine catecholamines.^{521,522,531,538,543,595,627,633} Patients with extra-adrenal primaries or non-diploid tumors may require more frequent follow-up with urine catecholamines and perhaps an MIBG scan.⁵¹⁷ Pheochromocytoma during pregnancy requires special considerations.^634,635 In general, if diagnosed in the first or second trimester, surgical removal of the tumor is indicated following medical preoperative preparation. If diagnosed in the third trimester, medical management is indicated, combined with Cesarean delivery of the mature fetus.

Medical Treatment of Recurrent or Metastatic Disease

The diagnosis of malignant pheochromocytoma can be made only when the tumor is locally invasive and unresectable, recurs after primary extirpation, or is found to be metastatic. Although the natural history of the disease in each of these situations may be variable and somewhat unpredictable, advanced malignant pheochromocytoma is associated with a high morbidity and mortality.^{511,520,527,539,545,628,632} These cancers also secrete catecholamines and often produce biogenic amines at a level much higher than benign neoplasms. Thus, the blood pressure elevations, cardiac effects, decreased bowel motility, and other clinical complications of catecholamine excess may be severe and unrelenting. The management of these problems utilizes the same principles of pharmacologic adrenergic blockade and inhibition of catecholamine synthesis described previously.

The rarity and highly variable natural history of malignant pheochromocytoma preclude determining accurate survival estimates. Analysis of SEER data demonstrated a 5-year relative survival rate of 52% with a median survival time of 4 years.⁵⁴⁴ Three retrospective analyses with a long duration of patient follow-up reported a 5-year survival rate of 60%, 32%, and 44%, respectively.^527,539,540 A recent series of 22 patients treated at the National Institutes of Health and the Mount Sinai Medical Center had a 5-year survival rate of 66% with a median survival time of 74 months from the time of initial diagnosis of pheochromocytoma (see Figure 89-11).⁵⁴⁴ All of these studies demonstrate that a significant number of patients with disseminated disease may live for long periods without specific antineoplastic therapy.^517,637 Overall, it appears that there are two distinct subsets within the population of patients with malignant pheochromocytoma: a group with aggressive disease that leads to early death (within 3 or 4 years) and a group with indolent disease that is compatible with long-term survival (up to 20 or more years) (see Figure 89-11).^520,527

From the Mayo Clinic series, it appears that survival has not changed over the past several decades despite advances in diagnosis, localization, and pharmacotherapy of catecholamine excess.^520,527 Surgical debulking of malignant pheochromocytomas that cannot be completely extirpated is controversial and carries a certain operative risk without clear benefit.^{517,531,627,628} The results of standard external beam radiation therapy for malignant pheochromocytoma have been limited to reports from a small series of selected patients treated with a variety of techniques (Table 89-15).^565,628,638 In general, these data do not support the use of this modality except for palliation of painful bony metastases or spinal cord compression.

Table 89-15

Treatment of Malignant Pheochromocytoma.

Targeted radiotherapy using high specific activity MIBG has been extensively investigated at the University of Michigan.⁵³¹ Because of the specificity of MIBG uptake by chromaffin tumors, this novel therapeutic approach initially generated much interest; in practice it was found that the majority of patients with malignant pheochromocytoma do not take up and retain sufficient MIBG to deliver an effective radiation dose to the tumor.^517,639,640 In their initial 63 patients screened with a tracer dose of MIBG, only 18 had sufficient uptake to permit therapeutic dosing, for example, where between 100 and 250 mCi of MIBG will deliver 20 Gy to the tumor.⁶⁰⁹ Out of a total of 28 patients treated by the Michigan group, 8 patients had tumor and biochemical responses, with most responses requiring several months and repeated dosing to become manifest. The duration of benefit has been short.^531,608 Other investigators have reported similar results in highly selected patients (see Table 89-15).^{609,641–645} The cause for the insufficient uptake of MIBG for therapy by malignant chromaffin neoplasms is not fully understood, but it may be due to the fact that these neoplasms may have a less differentiated amine uptake and storage phenotype compared to benign and normal chromaffin cells.⁵⁹⁶ Methods for accurate calculation of absorbed radiation dose are under development, and experimental models may provide new approaches to modulating tumor cell uptake of MIBG; but until such time as this and other difficulties are overcome, high dose MIBG for the treatment of pheochromocytoma has little clinical utility.^646,647

Until 1985, the data regarding standard systemic chemotherapy was limited to reports of empirically chosen single agents or combinations in small retrospective series and in anecdotal cases.^565,628 Because of its activity against gastroenteropancreatic tumors, streptozotocin was given to patients with metastatic pheochromocytoma with documented responses in some⁶⁴⁸ but not others (see Table 89-15).⁶⁴⁹ Based on the premise that malignant pheochromocytoma and neuroblastoma are two APUD neoplasms that have many clinicopathologic features in common, a regimen highly effective in children with advanced neuroblastoma, was adapted for use in malignant pheochromocytoma.^{596,639,650,651} This regimen, a combination of cyclophosphamide, vincristine, and dacarbazine (CVD) was used in treatment of 23 patients with advanced, progressive and symptomatic pheochromocytoma at the National Cancer Institute and Mount Sinai Medical Center.^511,512 There were 2 (9%) complete and 12 (52%) partial tumor remissions for a median duration of more than 22 months. Improvement in hypertension, reduction in requirement for antihypertensive medication, and improvement in overall performance status correlated well with complete and partial biochemical responses in 17 (74%) of the patients. Toxicity included moderate nausea and vomiting, myelosuppression, and mild neurotoxicity. Some moderate degree of postural hypotension developed that responded promptly to volume replacement therapy.⁵¹¹ Major hemodynamic side effects from chemotherapy were observed in two patients with paroxysmal hypertension. The lack of hypertensive events in most patients is probably due to the fact that patients were prepared with adequate volume repletion and pharmacologic adrenergic blockade prior to initiating chemotherapy. Since hypertensive episodes with release of stored catecholamine have been observed following chemotherapy, patients need to be prepared as if for surgery, and they require close monitoring during their initial chemotherapy treatment.^544,652,653 Patients with paroxysmal hypertension often present with unique problems because they cannot tolerate a full dose of antihypertensives. These antihypertensives lower their base-line blood pressure and worsen their orthostatic hypotension. Two patients in our series developed hypertensive crises and severe ileus after CVD treatment. This problem resolved after optimizing the antihypertensive regimens and adding metyrosine to deplete catecholamine storage.⁶⁵⁴

The CVD study is the largest prospectively studied chemotherapy series in malignant pheochromocytoma. The results have been confirmed by additional clinical experience.^512,638,655 Thus, CVD should be the treatment of choice for symptomatic, disseminated pheochromocytoma. With the introduction of colony-stimulating factors and newer antiemetics, dose escalation of CVD can be explored. Recent experience in neuroblastoma, where CVD has been replaced by the use of new agents and more intensive regimens, provides a basis for possible extrapolation to pheochromocytoma in future clinical trials.⁶⁵⁶

There is no information regarding the activity of interferon in malignant pheochromocytoma despite its reported activity in other neuroendocrine tumors.⁶⁵⁷ The somatostatin analogue, octreotide acetate, has been reported to produce symptomatic response in patients with endocrine syndromes caused by peptide-secreting pheochromocytomas.⁵⁵²

Epidemiology

MEN 1 syndrome is quite rare, with an estimated prevalence of between 0.02 and 0.2 per thousand and an incidence of 0.25% as determined from randomly chosen post-mortem studies.^658–660 However, the importance of this syndrome is related to its autosomal dominant hereditary pattern with high penetrance (Figure 89-15). Approximately one-third of patients with gastrinomas are associated with MEN 1 (see Chapters 103a and Chapters 103b, “Neoplasms of the Exocrine Pancreas” and “Neoplasms of the Ampulla of Vater”).^661–664 In contrast, insulinomas are usually sporadic, and fewer than 5% are found in MEN 1 patients.⁶⁶⁵

Figure 89-15

Pedigree of a typical kindred with MEN type 1 (reproduced with permission from Samaan et al.)

Pathologic characteristics MEN 1 is characterized by hyperplasia and/or neoplasms of the pituitary, parathyroid, and pancreatic islets. Hyperparathyroidism occurs in 90% of patients, pituitary adenomas in 40% of patients, and endocrine pancreatic tumors in 60% of patients.^659,666,667

Although the parathyroid glands are the most frequently involved organs (90%) and hyperparathyroidism is usually the first manifestation of the syndrome, its presence may not be detected until clinical disease of the pituitary or pancreas has brought the patient to medical attention.⁶⁶⁰ Hyperparathyroidism is often found during the second decade of life when screening immediate family members of those with proven MEN 1. In adults first suspected of the MEN 1 syndrome because of manifestations of gastrinoma, hyperparathyroidism is often diagnosed after obtaining serum calcium and parathyroid hormone levels, even though such patients may have had a decade-long history of renal stones.

MEN 1 patients characteristically have multiglandular nodular hyperplasia as the cause of their hyperparathyroidism. Often, the individual gland involvement is variable and is best described as asymmetrical hyperplasia, resulting in enlargement of only one or two glands, particularly in younger patients. This disease usually takes a slow but progressive course, and eventually all glands are involved.

The most frequent manifestation of MEN 1 pancreatic involvement is gastrinoma, usually developing during the third or fourth decade of life. With biochemical screening of MEN 1 kindreds, pancreatic abnormalities have been found at a much earlier age and often become the first manifestation of the syndrome.^668,669 Gastrinomas in the MEN 1 syndrome are typically small, multiple adenomas of the endocrine pancreas or duodenum⁶⁷⁰ that produce excess gastrin, causing gastric hyperacidity and multiple peptic ulcerations, classically known as the Zollinger-Ellison syndrome.⁶⁷¹ The malignant potential of MEN 1-associated gastrinomas is probably less than sporadic tumors. Additional tumors found are vasoactive intestinal polypeptidomas (VIPomas), glucagonomas, somatostatinomas, and pancreatic polypeptidomas (PPomas).⁶⁷² In some MEN 1 patients, tumors may develop and even metastasize to lymph nodes or liver with no clinical manifestations whatsoever. In others, more than one clinical functional syndrome may develop in the same patient either synchronously or more often metachronously.

Immunohistochemical studies of the pancreas from MEN 1 patients have shown that most tumors that stain positively for gastrin are in the head, uncinate process, or duodenum.⁶⁶⁴ Many of the larger tumors in the body or tail of the pancreas in gastrinoma patients stain positively only for hormones such as pancreatic polypeptide and somatostatin. Furthermore, even though islet-cell dysplasia (nesidioblastosis, hyperplasia, microadenomas) was found in all cases, these cells failed to stain positively for either gastrin or insulin. Therefore, when serum gastrin is elevated, the disease is in a more advanced stage, and at least 50% of patients have metastases already.⁶⁶⁹ Discrete tumors rather than diffuse islet-cell disease are usually present in patients with clinical syndromes.^673,674 The subsequent use of selective venous sampling for gastrin, insulin, or other hormones in MEN 1 patients has supported this thesis.⁶⁷⁵ It has also become apparent that gastrinomas are most likely to develop in the duodenum in MEN 1 patients.⁶⁷⁰ These tumors may be multiple, and in some cases they may be associated with pancreatic gastrinomas.

Micro- or macroadenomas of the pituitary gland are commonly detected in MEN 1 patients when biochemical and imaging studies have been performed.^658,659 Most tumors are functionally active and secrete prolactin.⁶⁷⁶ Less frequently, MEN 1 patients may develop tumor-secreting ACTH or growth hormone and present with Cushing syndrome or acromegaly. In the MEN 1 patient it is especially important to establish that the Cushing syndrome is pituitary dependent (Cushing disease) rather than caused by an adrenal adenoma or the ectopic secretion of ACTH or corticotropin-releasing factor (CRF) from islet-cell tumors or a bronchial carcinoid tumor.

Patients with MEN 1 syndrome have an increased frequency of both functional and non-functional adrenal cortical hyperplasia or adenomas.^{369,665,677,678} Furthermore, there may be an increased frequency of adrenal cortical carcinoma in MEN 1 patients, although only five cases have been well documented.

Carcinoid tumors have been reported more frequently in MEN 1 patients than would be expected.⁶⁷⁹ Male patients appear to have a predilection for developing carcinoid tumors within the thymus, whereas bronchial carcinoids occur almost exclusively in women. Gastric carcinoids can develop in MEN 1 patients with Zollinger-Ellison syndrome who are on long-term H2 blocker or omeprazole.⁶⁸⁰

Biologic Characteristics

The MEN 1 gene locus has been mapped to the long arm of chromosome 11 (11q13).⁶⁸¹ By using restriction fragment length polymorphism (RFLPs) and microsatellite polymorphisms from affected kindreds, MEN 1 gene carriers in the family can be identified with a predictive accuracy of 99.5%. When compared with leukocyte DNA, endocrine tumors from MEN 1 patients have loss of heterozygosity (LOH) at the region of chromosome 11q13.^{658,680,686–675} The allele lost is always from the normal chromosome belonging to the unaffected parent. This is analogous to the second hit in retinoblastoma. The gene involved in MEN 1, although not identified yet, is most likely a tumor suppressor gene. Adrenal adenomas are exceptions because they do not have LOH at chromosome 11q13. Furthermore, they occur only in patients with pancreatic endocrine tumors. This suggests adrenal hyperplasia and adenoma are secondary to other endocrine abnormalities.⁶⁶⁹ Deletion at chromosome 11q13 has also been found in a significant portion of sporadic adenomas of parathyroid gland, pancreas, and pituitary gland.^686,687 The gene or genes in this region certainly play an important role in endocrine tumorigenesis, either familial or sporadic. In addition to chromosome 11, other chromosomes and genetic changes may also be involved, such as PRAD 1 in parathyroid adenoma and Gs α- chain gene in pituitary adenoma. ^686,687

Clinical Features

The clinical features of patients with MEN 1 depend entirely upon expression of the natural history of the individual tumor and endocrine hyperfunction. Most patients with MEN 1 pancreatic disease requiring surgical intervention present with a syndrome caused by hypersecretion of a specific hormone such as gastrin, insulin, VIP, or glucagons.^666,667 However, in some patients a tumor may be detected by imaging studies obtained after serum laboratory studies have shown an elevation of one or more hormones such as pancreatic polypeptide or somatostatin. Overall, patients with familial MEN 1 neoplasms have long survival that is significantly better than that for patients with sporadic endocrine pancreatic tumors.^666,667

Diagnostic and screening tests A patient presenting with hyperparathyroidism or with hypergastrinemia should be questioned carefully regarding a family history of MEN 1 syndrome.⁶⁸⁸ In patients without family history, the diagnosis of MEN 1 can be made only by repeated biochemical testing to screen for other endocrine abnormalities. DNA analysis cannot be applied because it requires DNA from at least two affected family members to conclude which allele of the marker is inherited with the MEN 1 gene. But this limitation will no longer exist when the gene is cloned in the future. Once MEN 1 is diagnosed in a proband, all family members should undergo biochemical screening. Because endocrine abnormalities occur at different time points in different carriers, biochemical screening needs to be repeated for many years. Depending on the extensiveness of the screening program, the yield can be quite different. In one program, only 44% of gene carriers are identified at age 20.⁶⁸⁹ With more extensive screening, 100% of gene carriers can be identified at age 25, whereas in known MEN 1 kindreds, genetic screening with restriction fragment length polymorphisms (RFLPs) detects 99.5% of gene carriers at birth.^669,689,690 Only those who carry the mutated allele need to undergo yearly biochemical screening from childhood and continue for life. Peptic ulcer, renal complications, and malignant tumors are the common causes of death in MEN 1 patients.⁶⁹¹ Early detection and early treatment of endocrine abnormalities as the result of screening will reduce morbidity and possibly mortality from endocrinopathy.

The biochemical screening program that gives the highest yield includes PTH, albumin-corrected total serum calcium, prolactin, somatomedin C, blood glucose, insulin, proinsulin, gastrin, pancreatic polypeptide (PP), glucagon, and a meal test with PP and gastrin analysis. Radiologic examination of pituitary gland and upper abdomen can be done once every 3 to 5 years.⁶⁶⁹ The diagnostic approach to MEN 1 patients is determined by a clinical syndrome or clearly elevated hormone level. Hyperparathyroidism is diagnosed by hypercalcemia with elevated or non-suppressible PTH value. Pituitary adenomas usually have elevated serum prolactin or somatomedin C. The tumors are best visualized by MRI. Gastrinoma can be confirmed by measurements of basal and stimulated gastric acid output and provocative test with calcium or secretin. Insulinoma can be diagnosed by increased insulin and proinsulin level in the presence of hypoglycemia.

Localization procedures (discussed earlier in this chapter) for pancreatic endocrine tumors in MEN 1 syndrome present a special challenge due to their small size, multiplicity, and tendency to be malignant. However, these procedures are particularly important since complete excision of all tumors and cure are achievable.^521,674,692 Sonography, CT scan, and arteriography are successful in less than 50% of patients.⁶⁹³ Endoscopic ultrasound has been shown to be much more sensitive and specific. Tumors as small as 0.5 cm can be identified.⁶⁹⁴ Calcium and secretin angiography and transhepatic venous sampling can be used for occult tumors not imaged with other modalities.⁶⁹⁵¹²³I-Octreotide scan may be helpful.⁶⁹⁶ Intraoperative ultrasound of the pancreas should be used to locate nonpalpable tumors. Gastrinomas commonly occur in the duodenum, which can elude all imaging studies.⁶⁹⁷ Intraoperative transduodenal endoscopic illumination may help to identify the tumor during exploration.

Therapeutic Considerations

Generally, the management of patients with MEN 1 is the same as for each sporadic tumor comprising the syndrome. Even when distant metastases are present, systemic chemotherapy is rarely indicated in this syndrome. The elements of the management of patients with MEN 1 may include surgical removal of all four parathyroid glands (transplanting a portion of one of the glands to the forearm), subtotal pancreatectomy (removing as many multifocal tumors as possible in patients with endocrine pancreatic tumors), and medical management of pituitary adenomas with bromocriptine for prolactinomas and octreotide for acromegaly.

The surgical treatment of the MEN 1 syndrome is dependent on the genetic expression in the individual patient. Because components of the syndrome may be metachronous, surgical procedures involving different endocrine organs may be required over a period of many years. Regardless of initial findings, MEN 1 patients must be followed for life for involvement of the pituitary gland, the parathryoid glands, the endocrine pancreas or duodenum, the adrenal glands, the thymus, and the lungs (bronchial carcinoids). Hypercalcemia in MEN 1 usually is subtle and nonaggressive; early intervention is not necessary except in patients with gastrinoma because calcium increases gastrin secretion and worsens peptic ulcer disease. A source of persistent or recurrent disease is an overlooked supernumerary parathyroid gland, which is found most commonly in the upper thymus. Because of this, cervical thymectomy is considered an essential component of an adequate neck exploration in the MEN 1 patient.⁴⁰⁸ A common approach is subtotal parathyroidectomy, which leaves only a small remnant gland in place. Transient hypocalcemia is the desired result of these procedures, and if it does not occur, it usually means a supernumerary gland has been overlooked and recurrence is likely. If properly performed, oral calcium and vitamin D therapy can usually be tapered and discontinued within weeks. If performed correctly, permanent hypocalcemia should not develop. Although recurrent hypercalcemia may occur in patients after 10 years, successful surgical management is accomplished by trimming the hypertrophied remnant back to 50 mg.⁶⁹⁸

An alternative treatment, strongly advocated by some authors because of a recurrence rate as high as 40% after subtotal parathyroidectomy, is total parathyroidectomy, cervical thymectomy, forearm muscle autografting, and cryopreservation of parathyroid tissue for possible future need.^699,700 This operation requires just as thorough a cervical-mediastinal exploration as in subtotal parathyroidectomy to prevent cervical recurrence. Its advantage is that should recurrence develop from arm graft overgrowth, trimming back the implanted tissue can be performed under a local anesthesia. Its disadvantage is that all patients will require complete replacement therapy (vitamin D and oral calcium) for 3 months or longer, and some may be rendered permanently hypoparathyroid unless a subsequent thawed, cryopreserved transplant is successful. Both of these procedures are currently widely used in managing MEN 1 patients with hyperparathyroidism.

The surgical treatment of MEN 1 pancreatic disease is controversial.^673,674,701 One of the major issues centers on the fact that virtually all patients with pancreatic disease have a diffuse islet-cell dysplasia expressed as nesidioblastosis, islet-cell hyperplasia, microadenomatosis, and/or benign or malignant islet-cell tumors. As a result, it can be concluded that a cure of the pancreatic disease can only be achieved by a total pancreatectomy. However, the malignant potential of MEN 1 islet-cell neoplasm is relatively low, and with current medical therapy, there is little justification for total pancreatectomy either because of hormone hypersecretion or potential malignancy. In contrast, there is accumulating evidence that the majority of duodenal gastrinomas are malignant and lymph node and/or hepatic metastases from them develop in most patients if followed for a long enough period.^697,702

By a combination of preoperative localization and thorough exploration of both the pancreas and the duodenum, selected MEN 1 patients with hypergastrinemia can be rendered eugastrinemic, avoiding the necessity for either long-term drug therapy or total gastrectomy.^673,674,692 In patients with either insulinomas or gastrinomas, a distal pancreatectomy is performed, in most cases preserving the spleen, followed by a complete exploration of the remaining pancreatic head, uncinate process, and peri-pancreatic lymph nodes.⁶⁹² Any tumor found in the head or uncinate process by palpation or intraoperative ultrasound is enucleated. In all patients with gastrinoma, a longitudinal duodenotomy is made, and the mucosa from the pylorus to the third portion is evaginated into the incision and carefully palpated for submucosal tumors, which may be as small as 1 to 2 mm. When present, they are locally excised as are any lymph nodes in their drainage area.⁷⁰³ Using this approach, we have been able to achieve eugastrinemia in 12 patients with gastrinoma since 1978.⁶⁹² Of significance is the fact that more than one-half have had at least one peri-pancreatic lymph node involved with metastases, although primary tumors were as small as 2 mm in diameter. Even though some of these patients have subsequently shown a positive response to secretin stimulation, they have not required drug therapy or gastric operations. For patients with persistent, symptomatic hypergastrinemia from unresectable or metastatic gastrinoma, medical therapy with histamine-2 blockers or proton-pump inhibitors is indicated.⁷⁰⁴

MEN 1 patients with hyperinsulinism usually have had more than one tumor-secreting insulin. However, they are confined to the pancreas, and when all are enucleated or excised (distal pancreatectomy), the syndrome is cured and recurrences appear to be rare. Octreotide may be useful to palliate symptoms resulting from VIPoma, gastrinoma, glucagonoma, and carcinoid.⁷⁰⁵ Streptozocin plus doxorubicin achieved the best response in patients with unresectable, progressive malignant tumors.⁷⁰⁶ Symptomatic hepatic-dominant metastases can be palliated with surgical debulking or chemoembolization.⁷⁰⁷

Prolactinoma should be treated with bromocriptine or other dopamine analogs first. Both prolactin level and tumor size will decrease in most patients. Transphenoidal hypophysectomy is reserved for patients who fail to respond to medical therapy, but surgery is the treatment of choice for GH-secreting adenoma. Octreotide reduces tumor size and circulating GH and somatomedin C levels in a significant portion of patients.⁷⁰⁸ Cushing disease is best treated by transphenoidal hypophysectomy. Radiation, either limited sellar field or stereotaxic, can be used in patients who failed other modalities, but hormone level decreases very slowly, and hypopituitarism is common after conventional radiation.⁶⁷⁶

Surgical resection is indicated for carcinoid tumors. Unfortunately, the thymic carcinoids have usually been too far advanced when detected to allow for total excision and have been the cause of death in those with this tumor. Periodic mediastinal and chest CT scans should be used routinely in the follow-up of MEN 1 patients.